LIVER TRANSPLANTATION AFTER TACE FOR HEPATOCELLULAR CARCINOMA OUTSIDE MILAN CRITERIA: PRE-TRANSPLANT AFP LEVELS PREDICT VASCULAR INVASION.
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Bloom, Roy; Naraghi, Robert; Cibrik, Diane; Angelis, Michael; Mulgoankar, Shamkant; Kaplan, Bruce; Gaston, Robert; Gordon, Robert Author InformationKeywords:
Milan criteria
Vascular invasion
Hepatocellular carcinoma is one of the leading malignancies worldwide. Early detection of hepatocellular carcinoma and its management in the form of liver transplantation offers an attractive treatment option. The Milan criteria, proposed by Mazzaferro et al, have been the standard for selecting patients with hepatocellular carcinoma for transplantation. Recently, several studies have shown that even patients selected outside the Milan criteria can undergo transplantation with a relatively good outcome. This article examines the currently existing criteria other than the Milan criteria and also evaluates use of alpha-fetoprotein and positron emission tomography scans to predict the chance of recurrence.
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Liver transplant is one of the few effective treatments for hepatocellular carcinoma. Our aim in this study was to evaluate the risk factors for hepatocellular carcinoma recurrence after liver transplant.In this retrospective study, conducted between October 1988 and March 2015, four hundred seventy-three liver transplants were performed at our institution. Of these, 231 were pediatric and 242 were adult. Among these patients, liver transplant was performed in 58 patients (12.3%) for treatment of hepatocellular carcinoma.Hepatocellular carcinoma recurrence was detected in 14 patients (24.1%). Overall 5-year and 10-year survival rates of patients underwent liver transplant beyond the Milan criteria for hepatocellular carcinoma were 50.3% and 43.1%. Overall, 5- and 10-year survival rates of patients underwent liver transplant within the Milan criteria for hepatocellular carcinoma were 78.4% and 72.6%. The main predictive variable was whether the tumor had expensed beyond the Milan criteria.As expected, outcomes were significantly better in the Milan criteria group. Although the overall- and disease-free survival rates were promising in such a group of patients who had no better chance, it could be asserted that liver transplant is a safe and effective treatment option with promising results, even if the tumor expanse is beyond the Milan criteria.
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Since 1989, over 3,000 living donor liver transplantation (LDLTx) were performed in Japan. Among them, LDLTx for advanced hepatocellular carcinoma (HCC) with severe liver cirrhosis have recently increased. LDLTx for HCC has been offered only when liver function was severely impaired, or HCC became uncontrollable by other modalities such as hepatic resection or ablation therapies, which often exceeded the Milan criteria. One-and 3-year survivals were 84.6% and 73.3%, respectively. When exceeding the Milan criteria, tumor size over 5 cm, vascular invasion, grade of histologic differentiation of HCC, and high PIVKA-II over 300 mAU/ml were independent risk factors for HCC recurrence. Prevention of HCC or hepatitis C recurrence after transplantation should be resolved to improve graft and patient survival.
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We read with great interest the recent meta-analysis written by Koh and colleagues entitled "Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria: a meta-analysis of 18,421 patients" (1), which was published in the latest issue of Hepatobiliary Surgery Nutrition.The authors have reached an important conclusion that liver resection (LR) was associated with poorer overall survival (OS) and disease-free survival (DFS) compared to liver transplantation (LT) and found similar results among intention-to-treat (ITT) studies.In uninodular hepatocellular carcinoma (HCC), DFS is poorer in LR, but OS was comparable to LT.In addition, subgroup analysis revealed that in Europe and North America, LR had poorer OS versus LT, but OS was comparable in Asia.Before 2010, LR had inferior survival versus LT, but not after 2010.Cohorts that undergoing usual surveillance had worse OS after LR, but cohorts underwent enhanced surveillance had comparable OS after LT and LR.These findings emphasize that LT remains the ideal treatment option for HCC by removing both the tumor and the surrounding diseased liver, thus addressing the field change effect and lowering the risk of recurrence.Nevertheless, although the authors discussed some limitations, some deficiencies related to this meta-analysis still existed that we would like to raise.Firstly, there are some flaws in the literature search.To begin with, only two electronic databases (MEDLINE and Embase) were systematically searched for eligible literature.Second, only studies published in English were eligible for inclusion, which could inevitably introduce some language bias.Thus, to make this meta-analysis invulnerable, the authors are suggested to choose more electronic databases like Scopus, Web of Science, and Cochrane Library to search for eligible studies without language restriction.Secondly, regarding inclusion criteria, the eligible patients were diagnosed with HCC within Milan criteria.Nevertheless, after a careful review, we noticed that the authors appeared to have made an apparent mistake in this meta-analysis.The reference 27 is not about LR versus LT for HCC within Milan criteria (2).Third, in consideration of the heterogeneity is significantly high in the results section.It is critical to perform meta-regression and subgroup analyses to explore potential sources of heterogeneity.The covariates such as country (China versus the United States), year of publication (before 2010 versus 2010-2021), and sample size (>50 versus <50) might be taken into account when meta-regression and subgroup analyses are carried out.What's more, results were stratified by date of study, unimodular HCC, region and income were performed by the investigators.However, these forest plots weren't presented.We suggest that the investigators to provide these forest plots in supplementary materials.Finally, there is an ambiguity in this meta-analysis.In the results section, the authors claimed that LR was associated with poor OS outcome in HCC within Milan criteria.However, we are wondering what does the OS mean, 1-year survival or 3-year survival?The same as DFS.
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Objective: To assess the potential influence of replacing Milan criteria with simple risk scores on outcomes of hepatocellular carcinoma (HCC) patients undergoing liver transplantation. Summary Background Data: Several risk scores combining morphological and biological features were recently proposed for precise selection of HCC patients for transplantation. Methods: This retrospective study included 282 HCC liver transplant recipients. Recurrence-free survival (RFS), the primary outcome measure, was evaluated according to Metroticket 2.0 model and French AFP model with Milan criteria serving as benchmark. Results: Patients were well stratified with respect to RFS by Milan criteria, Metroticket 2.0 criteria, and AFP model cut-off ≤2 points (all P < 0.001) with c-statistics of 0.680, 0.695, and 0.681, respectively. Neither Metroticket 2.0 criteria (0.014, Z = 0.023; P = 0.509) nor AFP model (−0.014, Z = −0.021; P = 0.492) provided significant net reclassification improvement. Both patients within the Metroticket 2.0 criteria and AFP model ≤2 points exhibited heterogeneous recurrence risk, dependent upon alpha-fetoprotein ( P = 0.026) and tumor number ( P = 0.024), respectively. RFS of patients beyond Milan but within Metroticket 2.0 criteria (75.3%) or with AFP model ≤2 points (74.1%) was inferior to that observed for patients within Milan criteria (87.1%; P = 0.067 and P = 0.045, respectively). Corresponding microvascular invasion rates were 37.2% and 50.0%, compared with 13.6% in patients within Milan criteria (both P < 0.001). Moreover, Milan-out status was associated with significantly higher recurrence risk in subgroups within Metroticket 2.0 criteria ( P = 0.021) or AFP model ≤2 points ( P = 0.014). Conclusion: Utilization of simple risk scores for liver transplant eligibility assessment leads to selection of patients at higher risk of posttransplant HCC recurrence.
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